Effects of DPP4 Inhibitors as Neuroprotective Drug on Cognitive Impairment in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review

Purpose Type 2 diabetes mellitus is considered as one of the risk factors for cognitive impairment. DPP4 inhibitors are effective drugs for the treatment of type 2 diabetes mellitus. However, the relationship between DPP4 inhibitors and cognitive dysfunction remains unclear. Therefore, we used a meta-analysis to determine the association between DPP4 inhibitors and cognitive impairment in type 2 diabetes mellitus. Methods We systematically searched PubMed, CNKI, and the Cochrane Library at the time of establishment, 2022, and then made inclusion criteria and screened strategies to identify studies with more precise correlations. Results We included 10 studies with 5,583 participants. The data showed that DPP4 inhibitors significantly reduced the incidence rate of cognitive impairment in type 2 diabetes mellitus (SMD: 0.99; 95% CI [0.59, 1.38]). Furthermore, there was a linear correlation found between cognitive impairment in type 2 diabetes mellitus and fasting blood glucose, 2-hour postprandial blood glucose, and glycosylated hemoglobin. DPP4 inhibitors decreased fasting blood glucose (FPG) (SMD: 0.52; 95% CI [−0.68, −0.37]), blood glucose (2hPPG) at 2 hours after the meal (SMD: 0.82; 95% CI, [−1.2, −0.43]), and HbA1c (SMD: 0.34; 95% CI [−0.48, −0.21]). All data were statistically significant (P < 0.0001). Furthermore, we conducted subgroup analyses of the following measures at various treatment durations and ages: cognitive scores, fasting blood glucose, glycosylated hemoglobin, and two-hour postprandial blood glucose. Conclusion DPP4 inhibitors significantly improved type 2 diabetic mellitus individuals' cognitive impairment and reduced fasting blood glucose, 2-hour postprandial blood glucose, and glycosylated hemoglobin. Subgroup analysis showed that people aged 60 to 70 years had better treatment effects at 0–180 days. This trial is registered with CRD42023399473.


Introduction
A risk factor for cognitive dysfunction, such as dementia, mild cognitive impairment, and cognitive decline, is type 2 diabetes mellitus (T2D) [1].Cognitive dysfunction is deemed to be the presence of a number of cognitive disabilities that result in occupational dysfunction [2].Several researchers [3] have reported that people with type 2 diabetes mellitus generally sufer from cognitive dysfunction.Te intimate relationship between these two conditions has been proved many times as many as 60% of T2D patients have cognitive dysfunction [4].In addition, the quality of life of T2D patients is rapidly declining due to an increase in cognitive impairment disorders.Te lack of efective treatments for cognitive impairment in diabetic patients necessitates the search for efective medications.
In a Danish real-world study, DPP4 inhibitors showed better cognitive outcomes compared to sulfonylureas [13].
Te results of another retrospective study also showed that DPP4 inhibitors were protective against cognitive impairment compared with metformin [14].It seems that these studies are all about the benefcial efects of DPP4 inhibitors.However, other studies have suggested that DPP4 inhibitors may be associated with an increased risk of cognitive impairment in T2D patients.DPP4 is widely used in diabetes treatment; the additional benefcial role of drugs on cognitive function has been recommended.We conducted a meta-analysis to evaluate cognitive outcomes in T2D patients treated with DPP4 inhibitors.

Search
Cochrane A total of 1287 articles were retrieved from PubMed, 1 from CNKI, and 12 from Cochrane Library.

Data Extraction. Inclusion and exclusion criteria were drawn up based on PICOS.
Te inclusion criteria are as follows: (  International Journal of Endocrinology follow-up, dosage and risk (HR), and 95% confdence interval (CI).According to the Cochrane Handbook for Systematic Evaluation of Intervention [15], the quality of selected studies was evaluated in six aspects: assignment hiding, random sequence generation, outcome evaluation blindness, participant and personnel blindness, incomplete outcome data, and selective reporting.Tese biases will be independently assessed by 2 review authors for each included study.Among them, the defnition of allocation hiding is the selective bias caused by the imperfect follow-up allocation scheme, and the defnition of selective reporting is the reporting bias caused by the selective reporting results.Te literature we included included one risk on the allocation of hidden risks and six risks due to incomplete other data in the selective report.Te Cochrane bias risk assessment tool will be used to mark each bias as "yes" (low bias risk), "no" (high bias risk), or "unclear" (uncertain bias risk).Any disagreement will be discussed with the third review writer.If there is any disagreement, please contact the author for a request.

Data Analysis.
In this study, basic information about the relevant literature, baseline information and experimental results, year of journal publication, authors' details, duration of the study, study population, duration of follow-up, age at baseline including title of the article, baseline weight, gender distribution, duration of diabetes mellitus, defnition of the endpoints, and determination of Montreal Cognitive Assessment Score [16] and the results of the study were extracted.Ratio and 95% confdence intervals (CI) will be calculated to assess the relationship between DPP-4 inhibitors and cognitive impairment.In general, we compared the baseline data before and after medication, extracted the mean, standard deviation, and sample size (N) from the literature, and counted the mean (Mean) and standard deviation (SD) values diference between baseline and endpoint.Considering the diferences in experimental design and measurement units, diferences in the data were eliminated by standardized mean diference (SMD) [17].We used the random-efects model or fxed-efects model in RevMan5.4 software (the selection criterion was to test the heterogeneity of the high heterogeneity derandomization efect model with I 2 > 75% and that of the low heterogeneity defxation efect model with I 2 < 25%) to count the SMD and 95% CI.We used forest plots to analyse efect sizes.P < 0.05 was considered statistically signifcant.

Data Selection.
When evaluating the efect of DPP4 inhibitors on cognitive impairment in T2D, we selected the Montreal Score (MoCA) or the MMSE as an indicator to improve cognitive impairment [15].In addition, fasting blood glucose, 2-hour post meal blood glucose, and glycosylated hemoglobin are associated with cognitive impairment.According to previous studies, the TyG index (calculated as in (fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2)) is associated with the risk of cognitive decline in diabetic patients [26].People with prediabetes and diabetes who had high levels of glycosylated hemoglobin (HbA1c) compared to normal blood sugar showed signifcant cognitive decline over 10 years.When HbA1c is increased by 1 mmol/ml, the Z-score of global cognition (−0.0009SD/year), the Z-score of memory (−0.0005SD/ year), and the Z-score of executive function (−0.0008SD/ year) all decrease [27].Te study found a linear correlation between cognitive dysfunction and glycosylated hemoglobin levels.Tus, efectively reducing fasting blood glucose (FPG), 2-hour postprandial blood glucose (2hPPG), and glycosylated hemoglobin (HbA1C) can also improve cognitive impairment.

Risk of Bias
Assessment.All 10 included trials were declared randomized, and 10 used a double-blind study design.In the 10 trials, placebo-controlled was 2, and other hypoglycemic agents controlled was 8 (Figure 2).

Relationship between DPP4i and Cognitive Score.
Figure 3 illustrates the efect of DPP4 inhibitors on cognitive impairment in patients with T2D.Random-efects models were used, including 2634 in the control group and 2754 in the experimental group.After standardization, the MMSE score of the test group increased by 0.99 (95% [0.59, 1.38]), and I 2 value was 97%, P < 0.00001 (statistically signifcant), showing high heterogeneity.Te data suggest that DPP4 inhibitors can improve cognitive impairment in patients.

Relationship between DPP4i and Fasting Blood Glucose.
Previous studies have shown that patients with elevated serum triglycerides (TG) and blood sugar levels have a greater risk of cognitive impairment than those with lower levels.One index, TyG index (calculated as in (fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2)), is associated with the risk of cognitive decline in patients with diabetes.Figure 4 illustrates the efcacy of DPP4 inhibitors on fasting glucose.A fxed-efect model was used in 371 subjects in the experimental group and 369 subjects in the control group.After standardization, compared with the control group, fasting blood glucose in the experimental 4 International Journal of Endocrinology group was reduced by 0.52 (95% CI [−0.68, −0.37]),I 2 was 97% (P < 0.05).Tis fgure indicates that DPP4 inhibitors efectively reduce fasting blood glucose and thus efectively improve cognitive impairment in diabetic patients.

Relationship between DPP4i and Glycosylated
Hemoglobin.Te researchers found that people with prediabetes and diabetes who had high levels of glycosylated hemoglobin (HbA1c) compared to normal blood sugar had signifcant cognitive declines over 10 years.When HbA1c is increased by 1 mmol/ml, the Z-score of global cognition (−0.0009SD/year), the Z-score of memory (−0.0005SD/ year), and the Z-score of executive function (−0.0008SD/ year) all decrease [27].Te study found a linear correlation between cognitive dysfunction and glycosylated hemoglobin levels.Compared with prediabetic patients, with the increase in HbA1c level, the cognitive dysfunction of diabetic patients declined more signifcantly.Figure 5 illustrates the efcacy of DPP4 inhibitors on HBA1c.A fxed-efect model was used in 434 subjects in the experimental group and 441 in the control group.After standardization, compared with the control group, the HBA1c of the experimental group decreased by 0.34 (95% CI [−0.48, −0.21]), and the I 2 value was 89% (P < 0.05), indicating that DPP4 inhibitor can efectively reduce HBA1c, so as to improve the cognitive impairment of diabetic patients.), and the diference is signifcant.Subgroup analysis showed that, overall, there were statistically signifcant diferences in treatment outcomes by age and course of treatment, and meta-analysis showed that heterogeneity was not reduced among treatment groups, so diferent durations of treatment could not explain the heterogeneity between the two studies.However, the reduced heterogeneity found in diferent age groups is likely to be the reason for the high heterogeneity of the study results, which needs to be carefully understood (Figures S5  and S6).

Blood Glucose at 2 hours after Meal.
Overall blood glucose at 2 hours after meal decreased with DPP4i compared to the control group 0.82 (95% CI [−1.2, −0.43]), and the diference is signifcant.Subgroup analysis showed that there were statistical diferences among diferent treatment courses.Te meta-analysis showed that there was still high heterogeneity between the two groups of patients in diferent courses of treatment (Figure S7).

Discussion
Diabetes is a chronic disease that endangers the normal function of the human body.It can be divided into type 1 diabetes mellitus and T2D according to diferent pathological mechanisms.DPP-4 is a multifunctional serine protease that regulates immune cell-mediated β cell destruction and immune cell function, thereby prolonging the progression of type I diabetes mellitus.Both type I and T2D carry the risk of cognitive impairment.However, the negative impact of diabetes on cognition in older patients is greater in T2D than in type I diabetes.It has been reported  International Journal of Endocrinology [28] that DPP4i has neuroprotective efects and can lead to the improvement of cognitive and noncognitive dysfunctions of the nervous system.However, there are few studies on the cognitive dysfunction of DPP4i in type I diabetes, so we do not do further studies.T2D is related to the development of cognitive impairment.Some scholars believe that the mechanism of cognitive impairment with T2D may be infammation, NOS, oxidative stress, and infuence on blood vessels passing through the brain [29].Now, studies have shown the potential neuroprotective efect of DPP4i, which have been shown to reverse amyloid deposition in cognitive impairment in Alzheimer's disease [30].However, there is still disagreement about the cognitive efect of T2D.
In our meta-analysis, DPP4 inhibitors showed an improved efect on cognitive impairment in T2D, and DPP4i has previously been shown to have an improved efect on cognitive impairment [31].Of course, broader cognitive tests are needed to support this idea.Tere are several mechanisms to explain this efect.DPP4i is a class of oral hypoglycemic agents whose function is to prevent gastrointestinal degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin polypeptide, thereby improving blood sugar [32].GLP-1 has been shown to act as a neurotrophic factor and prevent neurodegeneration, possibly by facilitating long-term enhancement, raising neurite growth, and promoting synaptic formation in a manner similar to nerve growth factor [33].It has a potential protective efect on cognitive impairment [34].In addition, fasting blood glucose, 2-hour postprandial blood glucose, and glycosylated hemoglobin were associated with cognitive impairment, and cognitive dysfunction was found to be linearly correlated with the levels of these factors.Our data also proved that these three variables were well improved under the action of DPP4i.
More research is needed to determine whether the type of drug used in the control group had an efect on the results.Previous studies [35] have shown that metformin users have a lower risk of dementia compared to sulfonylureas users, and the researches support the hypothesis that metformin provides more neuroprotection for dementia than sulfonylureas, but further work is needed to assess causality.However, no studies have proved that DPP4i is more effective than metformin in improving the cognitive impairment of diabetic patients.Only Zheng et al.'s study [36] showed that the use of metformin was associated with better memory performance over time, while the use of DPP4i was associated with a slower rate of memory decline.Te interaction efect showed that the beneft of the DPP4 inhibitor in the APOE epsilon 4 vector was greater.Terefore, our research is more signifcant.
In addition, previous studies [37] have proved that the level of blood glucose and hemoglobin are related to the risk of dementia in the elderly.We considered whether the cognitive improvement after DPP4 inhibitor treatment was caused by the drug itself or by lowering blood glucose and haemoglobin.According to previous studies [38], brainderived neurotrophic factor (BDNF) decreases and DPP4 activity increases in the peripheral circulation of mild cognitive impairment, and the negative correlation is caused by oxidative stress and infammation.In addition, MCI patients with normal glucose tolerance also have lower peripheral circulation activity of BDNF and increased DPP4, and the use of DPP4 inhibitors can improve cognitive dysfunction.Terefore, we believe that it is the drug action of the DPP4 inhibitor itself that leads to the cognitive improvement.Further research is needed.
Finally, the efect of taking the same drug will naturally vary with the age, nationality, course of treatment, and dosage of diferent users.We hypothesized that the high heterogeneity of the efects of DPP4 inhibitors on cognitive impairment was due to other factors such as country, age, sex, and duration of treatment.Finally, we used subgroup analysis to reduce heterogeneity.Te main analysis included cognitive score, fasting blood glucose, glycosylated hemoglobin, and two hours postprandial blood glucose, and the variable factors were diferent in treatment duration and age.However, these subgroup analyses also had moderate and high heterogeneity, and only the subgroup analysis of glycosylated hemoglobin did heterogeneity decrease across age groups.In addition, subgroup analyses based on cognitive scores were conducted, and DPP4i has better results in patients aged 60 to 70 years old.At the same time, the treatment time of 0 to 180 days is better, which indicates the importance of age and time of medication in clinical studies.
All of these suggest that DPP4 inhibitors have a positive efect on cognitive impairment in T2D and have a potential role in preventing cognitive impairment.Te signifcance of this review and meta-analysis is to give further recommendations for clinical research, which will have positive implications for the protection of cognitive dysfunction in diabetic patients.
4.1.Limitations.Limitations are as follows: (1) cognitive impairment changes with age, and the prognostic value of DPP4 inhibitors also has certain risks.Although the data we collected were the result of multivariate adjustment, other confounding factors could not be excluded.(2) Some differences can be observed in the inclusion of RCTS, and there are random errors.(3) Tere was signifcant heterogeneity in the study, such as age, experimental design, drug dosage, and other factors, but due to limited data, we could not do subgroup analysis to test the heterogeneity.(4) Tis study is mainly to prove the efect of DPP4 hypoglycemic agents on diabetic patients with cognitive impairment, which should be compared with other hypoglycemic agents.However, due to the lack of data such as dosage and use time in literature, more studies are needed to solve the problem.(5) Te patients in our paper are from Asia, America, and Europe.Tere is a lack of research in other regions, and more data are needed to confrm the diferences in drug efcacy among diferent ethnic groups.

Conclusion
Based on the available data discussed, our data suggest that DPP4 inhibitors remarkably improve cognitive dysfunction in patients with T2D and decline fasting blood glucose, 2-

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International Journal of Endocrinology hour postprandial blood glucose, and glycosylated hemoglobin.Subgroup analysis showed that people aged 60 to 70 years had better treatment efects at 0-180 days.However, more precise conclusions need a larger data size and sample size, which, we hope, can be solved in the future.
Strategy.We systematically searched PubMed, CNKI, and the Cochrane Library at the time of establishment, 2022, and the search strategy is ((((DPP-4 Inhibitor) OR (DPP-IV Inhibitor) OR (Dipeptidyl Peptidase 4 Inhibitor)) AND (diabetes Cognitive Dysfunctions)) OR (diabetes cognitive Impairment)) OR (diabetes mild cognitive Impairments) Sort by: Most Recent(("dipeptidyl-peptidase iv inhibitors"[All Fields] OR "dipeptidyl-peptidase iv inhibitors"[MeSH Terms] OR ("dipeptidyl-peptidase"[All Fields] Library trials matching diabetes in Title Abstract Keyword AND DPP-4 Inhibitor or Dipeptidyl Peptidase IV Inhibitors or DPP-IV Inhibitors in Title Abstract Keyword AND Cognitive Dysfunctions or Cognitive Impairments or Mental Deterioration in Title Abstract Keyword -(Word variations have been searched).

Figure 1 :
Figure 1: Flowchart of study selection for the meta-analysis.

Figure 2 :
Figure 2: Assessment of risk of bias.As shown in the fgure, the risk of bias was evaluated in six dimensions.Low risk of bias was represented by green, unclear risk of bias was represented by yellow, and high risk of bias was represented by red.

Figure 6 :
Figure 6: Meta-analysis of the impact of DPP4i on 2-hour postprandial glucose.Forest map showing the diference in 2-hour postprandial glucose variations with diabetes treated or not treated with DPP4i in fve trials (n � 542).Black squares indicate mean diferences, horizontal lines through black squares indicate 95% CI, and green diamonds indicate pooled efect sizes shown using a fxed-efect Hedges model.
Figure 3: Meta-analysis of the impact of DPP4 inhibitors on cognitive impairment.Forest map displaying variations in MMSE with diabetes treated or not with DPP4i in 9 trials (n � 5388).Black squares indicate mean diferences, horizontal lines through black squares indicate 95% CI, and green diamonds indicate pooled efect sizes shown using a random-efects Hedges model.
at 2 hours after Meal.Figure6illustrates the efect of DPP4 inhibitors on blood glucose at 2 hours after a meal.A fxed-efect model was used in 271 subjects in the experimental group and 271 treatment efects at 0-180 days.Moreover, meta-analysis showed that the heterogeneity of treatment course subgroup analysis was not reduced in the two groups.Terefore, the duration of the treatment course could not explain the Figure 4: Meta-analysis of the impact of DPP4 inhibitors on fasting blood glucose.Forest map showing the diference in fasting blood glucose variations with diabetes treated or not treated with DPP4i in 8 trials (n � 740).Black squares indicate mean diferences, horizontal lines through black squares indicate 95% CI, and green diamonds indicate pooled efect sizes shown using a fxed-efect Hedges model.
Figure 5: Meta-analysis of the impact of DPP4 inhibitors on glycosylated hemoglobin.Forest map showing the diference in glycosylated hemoglobin variations with diabetes treated or not treated with DPP4i in 9 trials (n � 875).Black squares indicate mean diferences, horizontal lines through black squares indicate 95% CI, and green diamonds indicate pooled efect sizes shown using a fxed-efect Hedges model.